(2017) Toxicol Sci "4-Bromodiphenyl Ether Induces Germ Cell Apoptosis by Induction of ROS and DNA Damage in Caenorhabditis elegans."

[Toxicol Sci, 2017]

The corresponding authorship has been updated to reflect Yang Luan and Jinfu Zhango as co-corresponding authors in the final version.

Fechner S et al. (2018) MicroPubl Biol "The bodies of dpy-10(e128) are twice as stiff as wild type"

Loizeau F, Pruitt B, Nekimken AL, Goodman MB, Fechner S

[MicroPubl Biol, 2018]

DPY-10 is a collagen protein in the nematodes cuticle. Mutations in the dpy-10 gene induce various morphological changes that lead to animals with a dumpy (Dpy) or roller (Rol) phenotype (Levy, Yang and Kramer, 1993).

Kim, Jinmahn et al. (2015) International Worm Meeting "The evolutionary conserved LIM homeodomain protein LIM-4/LHX6 specifies the terminal identity of a cholinergic C. elegans sensory/inter/motor neuron-type."

Kim, Jinmahn, Huh, Yang Hoon, Yeon, Jihye, Choi, Seong-Kyoon, Kim, Kyuhyung, Li, Chris

[International Worm Meeting, 2015]

The differentiated features of postmitotic neurons are determined by expression of specific transcription factors. However, the mechanism by which specific molecules determine neuronal cell fate and the extent to which the functions of transcription factors are conserved in evolution are not fully understood. In C. elegans, the cholinergic and peptidergic SMB sensory/inter/motor neurons innervate muscle quadrants in the head, send processes posterior down the sub-lateral cords (White et al., 1986), and regulate the amplitude of sinusoidal movement (Gray et al., 2005). To identify the factors that specify the neuronal cell fate of SMBs, we performed genetic screens and isolated several lim-4 mutant alleles, in which flp-12 neuropeptide gene expression was completely abolished only in the SMB neurons. We also found that the expression of other SMB markers, odr-2 (GPI-Anchored protein), cho-1 (choline transporter), and unc-17 (synaptic vesicle acetylcholine transporter), were abolished and the function of the SMB neurons is compromised in lim-4 mutant. To investigate the molecular mechanism of lim-4, we did promoter analyses and bioinformatics searches with the SMB marker genes and identified cis-regulatory motifs including putative LIM-4 binding sites. We confirmed that these regulatory elements were sufficient to drive the expression of a non-SMB marker gene in the SMB neurons. In addition, we expressed lim-4 cDNA under the control of the heat shock promoter which not only fully restored flp-12 gene expression in lim-4 mutants, but induced the ectopic expression of flp-12 in other cell-types. Two human LIM-4 orthologs, LHX6 and LHX8, also rescued the lim-4 mutant phenotypes. Furthermore, expression of either the human LHX6 or C. elegans LIM-4 induced cholinergic and peptidergic features in the human neuroblastoma cell line. Taken together, our results indicate that LIM-4/LHX6 are sufficient and required for specification of the distinct cholinergic and peptidergic neuronal fate.

Ahmad W et al. (2020) Biochem Biophys Res Commun "Prediction of human tau 3D structure, and interplay between O--GlcNAc and phosphorylation modifications in Alzheimer's disease: C.elegans as a suitable model to study these interactions invivo."

Ahmad I, Ahmad W, Shabbiri K

[Biochem Biophys Res Commun, 2020]

Tau protein regulates, maintains and stabilizes microtubule assembly under normal physiological conditions. In certain pathological circumstances, tau is post-translationally modified predominantly via phosphorylation and glycosylation. Hyper-phosphorylation of tau in Alzheimer's disease (AD) resulted in aggregated neurofibrillary tangles (NFTs) formation. Unfortunately, absence of tau 3D structure makes difficult to understand exact mechanism involved in tau pathology. Here by using ab-initio modelling, we predicted a tau 3D structure that not only explains its binding with microtubules but also elucidates NFTs formation. O-linked -N-acetylglucosaminylation (O--GlcNAc) is thought to regulate tau phosphorylation on single or proximal Ser/Thr residues (called as Yin-Yang sites). In this study, we not only validate the previously described three-serine residues (208, 238 and 400) as Yin-Yang sites but also predicted 22 more possible Ser/Thr O-glycosylation sites. Among them seventeen residues were predicted as possible Yin-Yang sites and are proposed to mediate NFT formation in AD. These predicted Yin-Yang sites may act as attractive therapeutic targets for the drug development in AD. Predicted 3D structure of tau₄₄₁ was highly accessible for phosphorylation and hyperphosphorylation, and showed higher surface accessibility for interplay between O--GlcNAc and phosphorylation modifications. Kinases and phosphatases involved in tau phosphorylation are conserved in human and other organisms. Homology modelling revealed conserved catalytic domain for both human and C.elegans O-GlcNAc transferase (OGT), suggesting that transgenic C.elegans expressing human tau may be a suitable model system to study these modifications.

Xu W et al. (2019) Elife "Evolution of Yin and Yang isoforms of a chromatin remodeling subunit precedes the creation of two genes."

Zhao Y, Stevens L, Munoz J, McGrath PT, Long L, Xu W, Felipe I, Ellis RE

[Elife, 2019]

Genes can encode multiple isoforms, broadening their functions and providing a molecular substrate to evolve phenotypic diversity. Evolution of isoform function is a potential route to adapt to new environments. Here we show that <i>de novo</i>, beneficial alleles in the <i>nurf-1</i> gene became fixed in two laboratory lineages of <i>C. elegans</i> after isolation from the wild in 1951, before methods of cryopreservation were developed. <i>nurf-1</i> encodes an ortholog of BPTF, a large (&gt;300kD) multidomain subunit of the NURF chromatin remodeling complex. Using CRISPR-Cas9 genome editing and transgenic rescue, we demonstrate that in <i>C. elegans</i>, <i>nurf-1</i> has split into two, largely non-overlapping isoforms (NURF-1.D and NURF-1.B, which we call Yin and Yang, respectively) that share only two of 26 exons. Both isoforms are essential for normal gametogenesis but have opposite effects on male/female gamete differentiation. Reproduction in hermaphrodites, which involves production of both sperm and oocytes, requires a balance of these opposing Yin and Yang isoforms. Transgenic rescue and genetic position of the fixed mutations suggest that different isoforms are modified in each laboratory strain. In a related clade of <i>Caenorhabditis</i> nematodes, the shared exons have duplicated, resulting in the split of the Yin and Yang isoforms into separate genes, each containing approximately 200 amino acids of duplicated sequence that has undergone accelerated protein evolution following the duplication. Associated with this duplication event is the loss of two additional <i>nurf-1</i> transcripts, including the long-form transcript and a newly identified, highly expressed transcript encoded by the duplicated exons. We propose these lost transcripts are non-functional side products necessary to transcribe the Yin and Yang transcripts in the same cells. Our work demonstrates how gene sharing, through the production of multiple isoforms, can precede the creation of new, independent genes.

Robertson SM et al. (2012) Worm "Our evolving view of Wnt signaling in C. elegans: If two's company and three's a crowd, is four really necessary?"

Robertson SM, Lin R

[Worm, 2012]

In this commentary, we discuss how our recent paper by Yang et al. contributes a new wrinkle to the already somewhat curious Wnt signaling pathway in C. elegans. We begin with a historical perspective on the Wnt pathway in the worm, followed by a summary of the key salient point from Yang et al., 2011, namely demonstration of mutually inhibitory binding of a -catenin SYS-1 to the N-terminus and another -catenin WRM-1 to the C-terminus of the TCF protein POP-1, and a plausible structural explanation for these differential binding specificities. The mutually inhibitory binding creates one population of POP-1 that is bound by WRM-1, phosphorylated by the NLK kinase and exported from the nucleus, and another bound by coactivator SYS-1 that remains in the nucleus. We speculate on the evolutionary history of the four -catenins in C. elegans and suggest a possible link between multiple -catenin gene duplications and the requirement to reduce nuclear POP-1 levels to activate Wnt target genes.

Wilson DL (1998) Journal of Gerontology "Commentary - Survival of C. elegans in axenic culture."

Wilson DL

[Journal of Gerontology, 1998]

Vanfleteren and colleagues present an interesting example of environmental conditions altering the kinetics of survival. Most previous studies of survival in C. elegans have used abundant bacteria as a food source. Such studies have found that the Gompertz function (exponential growth in mortality rate with age) gives a relatively good fit to survival curves, but that there is some deceleration in the rate of growth of mortality later in the life span. Yulong Yang and I have completed dozens of studies of small populations of the wild-type strain, N2, as well as strains TJ401, TJ411, TJ412,and BA713 in the presence of abundant bacteria in liquid or on agar. Survival curves were better fit by Gompertz more often than by Weibull or logistic functions (unpublished observations).

Yang XL et al. (1998) Science "Essential role of CED-4 oligomerization in CED-3 activation and apoptosis."

Chang HY, Yang XL, Baltimore D

[Science, 1998]

Control of the activation of apoptosis is important both in development and in protection against cancer. In the classic genetic model Caenorhabditis elegans, the pro-apoptotic protein CED-4 activates the CED-3 caspase and is inhibited by the Bcl-2-like protein CED-9. Both processes are mediated by protein-protein interaction. Facilitating the proximity of CED-3 zymogen molecules was found to induce caspase activation and cell death. CED-4 protein oligomerized in cells and in vitro. This oligomerization induced CED-3 proximity and competed with CED-4:CED-9 interaction. Mutations that abolished CED-4 oligomerization inactivated its ability to activate CED-3. Thus, the mechanism of control is that CED-3 in CED-3:CED-4 complexes is activated by CED-4 oligomerization, which is inhibited by binding of CED-9 to CED-4.AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.FAU - Yang, XAU - Yang XFAU - Chang, H YAU - Chang HYFAU - Baltimore, DAU - Baltimore DLA - engID - CA51462/CA/NCIPT - Journal ArticleCY - UNITED STATESTA - ScienceJID - 0404511RN - 0 (Biopolymers)RN - 0 (Calcium-Binding Proteins)RN - 0 (Ced-4 protein)RN - 0 (Ced-9 protein)RN - 0 (Cysteine Proteinase Inhibitors)RN - 0 (Enzyme Precursors)RN - 0 (Helminth Proteins)RN - 0 (Oligopeptides)RN - 0 (Proto-Oncogene Proteins)RN - 0 (Proto-Oncogene Proteins c-bcl-2)RN - 0 (Recombinant Fusion Proteins)RN - 0 (bcl-x protein)RN - 109581-93-3 (Tacrolimus)RN - EC 3.4.22 (Cysteine Endopeptidases)RN - EC 3.4.22.- (Ced-3 protein)SB - IM

Joshi B et al. (2020) Evid Based Complement Alternat Med "Antibacterial, Antifungal, Antiviral, and Anthelmintic Activities of Medicinal Plants of Nepal Selected Based on Ethnobotanical Evidence."

Neyts J, Parajuli N, Jouneghani RS, Luyten W, Liu M, Joshi B, Panda SK, Leyssen P

[Evid Based Complement Alternat Med, 2020]

Background: Infections by microbes (viruses, bacteria, and fungi) and parasites can cause serious diseases in both humans and animals. Heavy use of antimicrobials has created selective pressure and caused resistance to currently available antibiotics, hence the need for finding new and better antibiotics. Natural products, especially from plants, are known for their medicinal properties, including antimicrobial and anthelmintic activities. Geoclimatic variation, together with diversity in ethnomedicinal traditions, has made the Himalayas of Nepal an invaluable repository of traditional medicinal plants. We studied antiviral, antibacterial, antifungal, and anthelmintic activities of medicinal plants, selected based upon ethnobotanical evidence. Methods: . Also, cytotoxicity was assessed on human hepatoma (Huh), rhabdosarcoma (RD), and Vero (VC) cell lines. Results: motility, comparable to levamisole. Conclusions: In countries like Nepal, with a high burden of infectious and parasitic diseases, and a current health system unable to combat the burden of diseases, evaluation of local plants as a treatment or potential source of drugs can help expand treatment options. Screening plants against a broad range of pathogens (bacteria, viruses, fungi, and parasites) will support bioprospecting in Nepal, which may eventually lead to new drug development.

Guo D et al. (2014) RNA Biol "RNAa in action: from the exception to the norm."

Lin SS, Guo D, Barry L, Li LC, Huang V

[RNA Biol, 2014]

Small RNA programmed Argonautes are sophisticated cellular effector platforms known to be involved in a diverse array of functions ranging from mRNA cleavage, translational inhibition, DNA elimination, epigenetic silencing, alternative splicing and even gene activation. First observed in human cells, small RNA-induced gene activation, also known as RNAa, involves the targeted recruitment of Argonaute proteins to specific promoter sequences followed by induction of stable epigenetic changes which promote transcription. The existence of RNAa remains contentious due to its elusive mechanism. A string of recent studies in C. elegans provides unequivocal evidence for RNAa's fundamental role in sculpting the epigenetic landscape and maintaining active transcription of endogenous genes and supports the presence of a functionally sophisticated network of small RNA-Argonaute pathways consisting of opposite yet complementary &quot;yin and yang&quot; regulatory elements. In this review, we summarize key findings from recent studies of endogenous RNAa in C. elegans, with an emphasis on the Argonaute protein CSR-1.